Critical Limb Ischemia (CLI) represents the terminal stage of atherosclerotic peripheral arterial disease and is characterized by rest pain and gangrene; both heralding signs of limb loss. The incidence of CLI in Western societies is approximately 220 new cases per million per year, and with a progressively aging population, persistent rates of tobacco abuse, and an increase in diabetes, a steady growth of the population at risk is expected. Despite recent advances in surgical bypass and endovascular reperfusion techniques, approximately 25% of patients presenting with CLI will not be candidates for either procedure and amputation of the limb is the only option. Most surgeons strive to preserve the knee joint as above knee amputation (AKA) is associated with significantly greater rates of disability, institutionalization, and morbidity than below knee amputation (BKA). Unfortunately up to 24% of patients with BKA require conversion to AKA due to ischemic wound complications. Mesenchymal stromal cells (MSCs) improve blood flow and promote wound healing in animal models. MSCs do not express MHC-II antigens and allogeneic MSCs have been used in multiple clinical trials in cardiovascular disease without adverse host immune response. With this compelling medical need and background of supportive data we propose a Phase I clinical trial with the primary Aim of determining safety and assessing the efficacy of allogeneic MSCs in preventing wound complications after BKA. Three hundred million MSCs will be injected into the muscle of the amputation wound and proximal leg at the time of BKA. A composite measure of death, conversion to AKA, and incidence of gangrene during the six month study period will be compared to cohorts undergoing BKA not enrolled in the trial. Perfusion of the BKA flap will be quantified with indocyanine angiography (ICA) and transcutaneous oxygen pressures (TcPO2) at baseline and weeks 6, 12, and 24 and assessed for correlation with incidence of gangrene and AKA. Completion of this Aim will demonstrate that allogeneic MSCs are safe, if there is evidence of efficacy in preventing wound complications, and if further assessment in a larger randomized, placebo controlled clinical trial is warranted. Using high throughput genomic, molecular, and cellular analyses, Aim 2 will test our hypothesis that intra-muscular injection of MSCs act in a paracrine fashion to recruit bone marrow derived CD34+CD133+ proangiogenic hematopoietic cells to ischemic muscle and that this phenomenon correlates with capillary formation and tissue perfusion. Completion of this Aim will provide a first in man comprehensive description of the mechanisms by which these MSCs promote tissue repair in diseased human tissue.